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Stromal Pbrm1 mediates chromatin remodeling necessary for embryo implantation in mouse uterus [ATAC-Seq]

ABSTRACT: Early gestational loss occurs in ~20% of all clinically recognized human pregnancies and is a significant cause of morbidity. Either embryonic or maternal defects can cause loss, but a functioning and receptive uterine endometrium is crucial for embryo implantation. The SWI/SNF remodeling complex containing PBRM1and BRG1 is essential for implantation of the embryonic blastocyst on the wall of the uterus in mice. Although pre-implantation development is unaffected, conditional ablation of Pbrm1 in uterine stromal cells disrupts progesterone pathway and uterine receptivity. Hand2 is a bHLH transcription factor required for embryo implantation. We report a new enhancer of Hand2 in stromal cells that requires PBRM1 for epigenetic histone modifications and coactivator recruitment. In Pbrm1cKO mice, perturbations at the enhancer site compromised Hand2 transcription, disrupts the fibroblast growth factor signaling pathway and prevents normal Stromal- Epithelial crosstalk and embryo implantation. The resultant mutant female mice are infertile and provide insight into potential causes of early pregnancy loss in humans.

ORGANISM(S): Mus musculus

PROVIDER: GSE229367 | GEO | 2024/01/14

REPOSITORIES: GEO

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Stromal Pbrm1 mediates chromatin remodeling necessary for embryo implantation in mouse uterus [CHIC-Seq]

Project description:Early gestational loss occurs in ~20% of all clinically recognized human pregnancies and is a significant cause of morbidity. Either embryonic or maternal defects can cause loss, but a functioning and receptive uterine endometrium is crucial for embryo implantation. The SWI/SNF remodeling complex containing PBRM1and BRG1 is essential for implantation of the embryonic blastocyst on the wall of the uterus in mice. Although pre-implantation development is unaffected, conditional ablation of Pbrm1 in uterine stromal cells disrupts progesterone pathway and uterine receptivity. Hand2 is a bHLH transcription factor required for embryo implantation. We report a new enhancer of Hand2 in stromal cells that requires PBRM1 for epigenetic histone modifications and coactivator recruitment. In Pbrm1cKO mice, perturbations at the enhancer site compromised Hand2 transcription, disrupts the fibroblast growth factor signaling pathway and prevents normal Stromal- Epithelial crosstalk and embryo implantation. The resultant mutant female mice are infertile and provide insight into potential causes of early pregnancy loss in humans.

2024-01-14 | GSE229368 | GEO

Stromal Pbrm1 mediates chromatin remodeling necessary for embryo implantation in mouse uterus [RNA-Seq]

2024-01-14 | GSE229369 | GEO

Gene expression profiling of uterine stromal cells isolated from Hand2 floxed and Hand2 ablated mice on day 4 of pregnancy

Project description:Our previous study revealed that the basic helix-loop-helix transcription factor Hand2 is a downstream target of progesterone signaling in mouse uterine stroma at the time of implantation. Further, conditional deletion of Hand2 in mouse uterus leads to implantation failure due to impaired uterine epithelial receptivity. To identify the downstream targets of Hand2 in the uterus, we performed gene expression profling of uterine stromal cells isolated from Hand2-null mice and the corresponding controls on day4 of pregnancy (the time of implantation). The microarray results revealed elevated expression of mRNAs corresponding to several members of the fibroblast growth factor family in uterine stroma of Hand2-ablated mice. These factors act as paracrine mediators of mitogenic effects of estrogen on the epithleium. Thus, Hand2 is a critical regulator of the uteirne stromal-epithelial communication that directs proper steroid regulation conducive for establshment of pregnancy. We performed conditional ablation of Hand2 in the mouse uterus using the PRcre mouse model. As Hand2 expression is restricted to stromal comaprtment, we isolated uterine stromal cells from day4 pregnant mice (n=5 for each genotype), purified total RNA from these cells, pooled these samples and then hybridized to high density affymetrix microarrays. Control vs. KO.

2011-06-03 | E-GEOD-25881 | biostudies-arrayexpress

Gene expression profiling of uterine stromal cells isolated from Hand2 floxed and Hand2 ablated mice on day 4 of pregnancy

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SOX17 regulates uterine epithelial-stromal crosstalk acting via a distal enhancer upstream of Ihh [array]

Project description:Mammalian embryo development is dependent on the ability of the uterus to allow and support the implantation of the embryo. Here we demonstrate that ablation of Sox17 specifically in the uterine epithelium results in altered uterine epithelial cell proliferation, uterine gland development and embryo implantation. Uteri lacking Sox17 showed reduction in LIF and IHH signaling which are critical for embryo implantation. ChIP-seq analysis demonstrated that SOX17 binds to a region 19kb 5’ to the Ihh locus. In vivo deletion of this enhancer by the CRISPR-Cas technology reduced Ihh expression in uteri and altered proper endometrial epithelial-stromal interactions required for pregnancy leading to compromised fertility. The SOX17 binding peak at 19kb from the Ihh promoter also bound GATA2, FOXA2 and PGR. Bioinformatic analysis of regions overlapping SOX17, GATA2, FOXA2 and PGR bindings shows 737 genes with these common binding sites. This cluster of transcription factors identified in this enhancer region may represent a combination of regulatory elements essential for uterine epithelial gene expression and differentiation.

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SOX17 regulates uterine epithelial-stromal crosstalk acting via a distal enhancer upstream of Ihh [ChIP-seq]

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Chromatin remodeling of prostaglandin signaling in smooth muscle enables mouse embryo passage through the female reproductive tract [CHIC-seq Pbrm1 & Brg1]

Project description:After fertilization, early mammalian development takes place as the embryo transits the oviduct prior to implantation on the wall of the uterus. This transport is precisely orchestrated by secreted oviduct fluid, unidirectional beating of epithelial cilia and smooth muscle contractions. Using multiple gene-edited mice to affect the female reproductive tract, we document that conditional disruption of Pbrm1, a component of the SWI/SNF chromatin remodeling complex, prevents embryo transport. Loss of Pbrm1 in epithelial cells lining the oviduct had no effect, but ablation in smooth muscle phenocopied the transport defect without perturbing embryogenesis. Analysis with RNA-seq, ATAC-seq, ChIC-seq and pharmacologic rescue experiments implicated prostaglandin signaling pathways. In comparison to wildtype, gene-edited mice had compromised chromatin accessibility at enhancer/promoters of Ptgs2, Pla2g16, Pla2r1 and Ptger3 (EP3) as well as decreased enhancer-promoter interactive looping critical for Ptgs2 (prostaglandin-endoperoxide synthase 2, aka Cox-2) expression in a SWI/SNF complex dependent manner in smooth muscle. These observations provide mechanistic insight into potential causes of ectopic pregnancy in fallopian tubes that is a significant cause of morbidity and mortality in human pregnancies.

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Genome-wide chromatin profiles of PBRM1 [RNA-Seq]

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Enhancing Uterine Receptivity for Embryo Implantation through Controlled Collagenase Intervention

Project description:Ineffective endometrial matrix remodeling, a key factor in infertility, impedes embryo implantation in the uterine wall. Our study reveals the cellular and molecular impact of human collagenase-1 administration in mouse uteri, demonstrating enhanced embryo implantation rates. Collagenase-1 promotes remodeling of the endometrial extracellular matrix (ECM), degrading collagen fibers and proteoglycans. This process releases matrix-bound bioactive factors, (e.g. VEGF, decorin), facilitating vascular permeability and angiogenesis. Collagenase-1 elevates embryo implantation regulators, including NK cell infiltration and the key cytokine LIF. Remarkably, uterine tissue maintains structural integrity despite reduced endometrial collagen fiber tension. In-utero collagenase-1 application rescues implantation in the heat stress and embryo transfer models, known for low implantation rates. Importantly, ex-vivo exposure of human uterine tissue to collagenase-1 induces collagen de-tensioning and VEGF release, mirroring remodeling observed in mice. Our research highlights collagenase potential to induce and orchestrate cellular and molecular processes enhancing uterine receptivity for effective embryo implantation. This innovative approach underscores ECM remodeling mechanisms critical for embryo implantation

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